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    Small Molecule Antineoplastic FMS-like Tyrosine Kinase-3 (FLT-3) Inhibitors

    BOXED WARNING

    Differentiation syndrome

    Differentiation syndrome with or without concomitant hyperleukocytosis has been reported with gilteritinib therapy; this syndrome may be life-threatening or fatal if not treated. Monitor patients for signs and symptoms of differentiation syndrome such as pyrexia or elevated body temperature, dyspnea, hypoxia, pulmonary infiltrates, pulmonary edema, pleural or pericardial effusion, rapid weight gain or peripheral edema, rash, hypotension, or renal dysfunction. If differentiation syndrome is suspected, start corticosteroid therapy (e.g., dexamethasone 10 mg IV every 12 hours or PO/IV equivalent) and closely monitor hemodynamic parameters until improvement. Taper corticosteroids after symptoms resolve; premature corticosteroid discontinuation may lead to symptom recurrence. Interrupt gilteritinib therapy if severe signs or symptoms persist after 48 hours of corticosteroid therapy. Resume gilteritinib therapy when sign and symptoms of toxicity resolve to grade 2 or less. Differentiation syndrome may occur as soon as 1 day and up to 82 days after starting gilteritinib.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral tyrosine kinase inhibitor
    Used for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia that is FLT3 mutation-positive
    Differentiation syndrome has been reported

    COMMON BRAND NAMES

    XOSPATA

    HOW SUPPLIED

    XOSPATA Oral Tab: 40mg

    DOSAGE & INDICATIONS

    For the treatment of acute myelogenous leukemia (AML).
    NOTE: Gilteritinib has been designated an orphan drug by the FDA for the treatment of AML.
    For the treatment of relapsed or refractory FLT3 mutation-positive AML.
    NOTE: Patients should be selected based on the presence of FLT3 mutations in the blood or bone marrow. Information on FDA-approved tests is available at www.fda.gov/CompanionDiagnostics.
    Oral dosage
    Adults

    120 mg orally once daily. Continue therapy for a minimum of 6 cycles in patients who do not have unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption, dose reduction, or permanent discontinuation may be necessary in patients who develop toxicity. At a median follow-up, 17.8 months (range, 14.9 to 19.1 months), the median overall survival (OS) time was significantly improved in adult patients with relapsed or refractory FLT3-mutated AML who received gilteritinib compared with chemotherapy (9.3 months vs. 5.6 months; hazard ratio (HR) = 0.64; 95% CI, 0.49 to 0.83; p = 0.0004) in a multicenter, randomized (2:1), phase 3 trial (n = 371; the ADMIRAL trial). Chemotherapy consisted or high-intensity therapy with mitoxantrone, etoposide, and cytarabine (MEC; n = 33) or granulocyte colony-stimulating factor, fludarabine, cytarabine, and idarubicin (FLAG-IDA; n = 42) or low-intensity therapy with low-dose cytarabine (n = 17) or azacitidine (n = 32). In a subgroup analysis, OS was also significantly improved in patients who received gilteritinib compared with either high-intensity (HR = 0.66; 95% CI, 0.47 to 0.93) or low-intensity (HR = 0.56; 95% CI, 0.38 to 0.84) chemotherapy [63787]

    MAXIMUM DOSAGE

    Adults

    120 mg/day PO.

    Geriatric

    120 mg/day PO.

    Adolescents

    Safety and efficacy not established.

    Children

    Safety and efficacy not established.

    Infants

    Safety and efficacy not established.

    Neonates

    Safety and efficacy not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment are not available; it appears that no initial dosage adjustments are needed. Gilteritinib has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C).[63787]

    Renal Impairment

    Specific guidelines for dosage adjustments in mild (creatinine clearance (CrCl) of 50 to 80 mL/min) or moderate (CrCl of 30 to 50 mL/min) renal impairment are not available; it appears that no initial dosage adjustments are needed. Gilteritinib has not been evaluated in patients with severe renal impairment (CrCl of 29 mL/min or less).[63787]

    ADMINISTRATION

    Emetic Risk
    Minimal/Low
    Administer prn antiemetics as necessary.

    Oral Administration
    Oral Solid Formulations

    Do not break or crush gilteritinib tablets; swallow whole with a whole cup of water.
    Take with or without food.
    Take orally about the same time each day. If a dose is missed or not taken at the usual time, administer the dose as soon as possible on the same day, and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the next day.
    Do not administer 2 doses within 12 hours.[63787]

    STORAGE

    XOSPATA:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Differentiation syndrome

    Differentiation syndrome with or without concomitant hyperleukocytosis has been reported with gilteritinib therapy; this syndrome may be life-threatening or fatal if not treated. Monitor patients for signs and symptoms of differentiation syndrome such as pyrexia or elevated body temperature, dyspnea, hypoxia, pulmonary infiltrates, pulmonary edema, pleural or pericardial effusion, rapid weight gain or peripheral edema, rash, hypotension, or renal dysfunction. If differentiation syndrome is suspected, start corticosteroid therapy (e.g., dexamethasone 10 mg IV every 12 hours or PO/IV equivalent) and closely monitor hemodynamic parameters until improvement. Taper corticosteroids after symptoms resolve; premature corticosteroid discontinuation may lead to symptom recurrence. Interrupt gilteritinib therapy if severe signs or symptoms persist after 48 hours of corticosteroid therapy. Resume gilteritinib therapy when sign and symptoms of toxicity resolve to grade 2 or less. Differentiation syndrome may occur as soon as 1 day and up to 82 days after starting gilteritinib.

    Apheresis, AV block, bradycardia, cardiomyopathy, celiac disease, electrolyte imbalance, females, fever, geriatric, heart failure, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, long QT syndrome, myocardial infarction, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE)

    QT prolongation has been reported with gilteritinib therapy. Therapy interruption and a dose reduction are necessary in patients who develop a QTc interval longer than 500 milliseconds. Obtain an ECG prior to starting gilteritinib, on days 8 and 15 of cycle 1, and prior to the start of cycles 2 and 3. Monitor electrolytes (e.g., potassium and magnesium levels) prior to starting gilteritinib, at least once weekly for the first month, once every other week for the next month, and then once monthly during therapy. Correct electrolyte imbalance prior to and during treatment. Use gilteritinib with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.[28432] [28457] [56592] [63787]

    Arthralgia

    Muscle symptoms such as myalgia and arthralgia may occur with gilteritinib use. Monitor serum creatine phosphokinase (CPK) levels prior to starting gilteritinib, at least once weekly for the first month, once every other week for the next month, and then once monthly during therapy.

    Renal impairment

    Renal impairment has been reported with gilteritinib therapy. Monitor blood chemistries (e.g., renal function tests) prior to starting gilteritinib, at least once weekly for the first month, once every other week for the next month, and then once monthly during therapy. [63787]

    Hepatotoxicity

    Hepatotoxicity has been reported with gilteritinib therapy. Monitor blood chemistries (e.g., liver function tests) prior to starting gilteritinib, at least once weekly for the first month, once every other week for the next month, and then once monthly during therapy.[63787]

    Pregnancy

    Gilteritinib may cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies. Females of reproductive potential should avoid becoming pregnant while taking gilteritinib. Discuss the potential hazard to the fetus if a patient becomes pregnant while taking this drug. Although gilteritinib has not been evaluated in pregnant women, fetal toxicity occurred when pregnant rats received a gilteritinib dose resulting in approximately 0.4-times the exposure that was observed in humans who received the recommended dose. Fetal toxicity in this animal study included embryo-fetal death; decreased fetal body and placental weight; decreased numbers of ossified sternebrae and sacral and caudal vertebrae; and an increased incidence of fetal gross external (e.g., anasarca, local edema, exencephaly, cleft lip, cleft palate, short tail, and umbilical hernia), visceral (e.g., microphthalmia, atrial and/or ventricular defects, malformed/absent kidney, and malpositioned adrenal gland and ovary), and skeletal (e.g., sternoschisis, absent rib, fused rib, fused cervical arch, misaligned cervical vertebra, and absent thoracic vertebra) abnormalities.[63787]

    Contraception requirements, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during gilteritinib treatment. Pregnancy testing should be performed in women of reproductive potential within 7 days prior to initiating therapy. These women should use effective contraception during therapy and for 6 months after the final gilteritinib dose. Due to the risk of male-mediated teratogenicity, male patients should use effective contraception to avoid potential drug exposure in female partners of reproductive potential during therapy and for 4 months after the final gilteritinib dose.

    Breast-feeding

    It is not known if gilteritinib or its active metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Because there is a potential for adverse reactions in nursing infants from gilteritinib, women should be advised against breast-feeding during gilteritinib therapy and for 2 months after the last dose.[63787]

    ADVERSE REACTIONS

    Severe

    elevated hepatic enzymes / Delayed / 21.0-21.0
    hypophosphatemia / Delayed / 14.0-14.0
    hyponatremia / Delayed / 12.0-12.0
    dyspnea / Early / 12.0-12.0
    myalgia / Early / 7.0-7.0
    arthralgia / Delayed / 7.0-7.0
    oral ulceration / Delayed / 0-7.0
    hypotension / Rapid / 7.0-7.0
    hypocalcemia / Delayed / 6.0-6.0
    hypertriglyceridemia / Delayed / 6.0-6.0
    fatigue / Early / 6.0-6.0
    malaise / Early / 6.0-6.0
    pancreatitis / Delayed / 4.0-4.0
    pericardial effusion / Delayed / 0-4.0
    heart failure / Delayed / 4.0-4.0
    erythema / Early / 0-3.0
    differentiation syndrome / Delayed / 3.0-3.0
    myocarditis / Delayed / 0-2.0
    pericarditis / Delayed / 0-2.0
    rash / Early / 0-1.2
    GI perforation / Delayed / 0-1.0
    cardiac arrest / Early / 0-1.0
    cough / Delayed / 0-1.0
    fever / Early / 0-0.8
    constipation / Delayed / 0-0.4
    edema / Delayed / 0-0.4
    peptic ulcer / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    nephrotoxicity / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    pleural effusion / Delayed / Incidence not known

    Moderate

    peripheral neuropathy / Delayed / 18.0-18.0
    QT prolongation / Rapid / 1.0-9.0
    encephalopathy / Delayed / 1.0-1.0
    colitis / Delayed / Incidence not known
    hyperamylasemia / Delayed / Incidence not known
    hyperesthesia / Delayed / Incidence not known
    hypoxia / Early / Incidence not known
    neutropenia / Delayed / Incidence not known
    skin ulcer / Delayed / Incidence not known

    Mild

    dysgeusia / Early / 11.0-11.0
    muscle cramps / Delayed / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    acneiform rash / Delayed / Incidence not known
    hyperkeratosis / Delayed / Incidence not known
    acne vulgaris / Delayed / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    lethargy / Early / Incidence not known
    weight gain / Delayed / Incidence not known
    leukocytosis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with gilteritinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor.
    Afatinib: (Moderate) If the concomitant use of gilteritinib and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of gilteritinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-gp substrate and gilteritinib is a P-gp inhibitor. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    Alfuzosin: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and alfuzosin is necessary. Gilteritinib has been associated with QT prolongation. Based on electrophysiology studies performed by the manufacturer, alfuzosin may prolong the QT interval in a dose-dependent manner.
    Alpelisib: (Major) Avoid coadministration of alpelisib with gilteritinib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and gilteritinib is a BCRP inhibitor.
    Amiodarone: (Major) If possible, avoid coadministration of amiodarone and gilteritinib. Monitor for QT prolongation if concurrent use is necessary. Gilteritinib has been associated with QT prolongation. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amisulpride: (Major) Use caution and monitor electrocardiograms (ECGs) for evidence of QT prolongation if concurrent use of gilteritinib and amisulpride is necessary. Gilteritinib has been associated with QT prolongation. Amisulpride causes dose- and concentration- dependent QT prolongation.
    Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with gilteritinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; gilteritinib is a P-gp and BCRP inhibitor.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Consider an alternative to clarithromycin during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
    Anagrelide: (Major) Do not use anagrelide with gilteritinib due to the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects.
    Apalutamide: (Major) Avoid coadministration of gilteritinib and apalutamide due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; apalutamide is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Apomorphine: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and apomorphine is necessary since concurrent use may increase the risk of QT prolongation. Gilteritinib has been associated with QT prolongation. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
    Aripiprazole: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and aripiprazole is necessary. Gilteritinib has been associated with QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.
    Arsenic Trioxide: (Major) Avoid concomitant use of arsenic trioxide with gilteritinib; discontinue or select an alternative drug that does not prolong the QT interval prior to starting arsenic trioxide therapy. If concomitant drug use is unavoidable, frequently monitor electrocardiograms. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Gilteritinib has been associated with QT prolongation.
    Artemether; Lumefantrine: (Major) Avoid concomitant use of artemether; lumefantrine with gilteritinib due to the potential for additive QT prolongation. Consider ECG monitoring if gilteritinib must be used with or after artemether; lumefantrine treatment. Both artemether; lumefantrine and gilteritinib have been associated with QT prolongation.
    Asenapine: (Major) Avoid concomitant use of asenapine with gilteritinib due to the potential for additive QT prolongation. Both drugs have been associated with QT prolongation.
    Atazanavir: (Major) Consider an alternative to atazanavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Atazanavir; Cobicistat: (Major) Consider an alternative to atazanavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. (Major) Consider an alternative to cobicistat during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Atomoxetine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and atomoxetine is necessary. Gilteritinib has been associated with QT prolongation. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose.
    Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with gilteritinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; gilteritinib is a P-gp and BCRP inhibitor.
    Atorvastatin; Ezetimibe: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with gilteritinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; gilteritinib is a P-gp and BCRP inhibitor.
    Azithromycin: (Major) Avoid coadministration of azithromycin with gilteritinib due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Gilteritinib has been associated with QT prolongation.
    Bedaquiline: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and bedaquiline is necessary. Both drugs have been associated with QT prolongation. Coadministration may result in additive or synergistic prolongation of the QT interval.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of gilteritinib and phenobarbital due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; phenobarbital is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking gilteritinib. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor. Coadministration with another P-gp and BCRP inhibito increased berotralstat exposure by 69%.
    Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving gilteritinib. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving gilteritinib. Concurrent use may increase betrixaban exposure resulting in an increased bleeding risk; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a P-gp substrate; gilteritinib is a P-gp inhibitor. Coadministration of other P-gp inhibitors increased betrixaban exposure by 2 to 3-fold.
    Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with gilteritinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and gilteritinib may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and gilteritinib may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Buprenorphine: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and buprenorphine is necessary. FDA-approved labeling for some buprenorphine products recommends avoiding use with any drug that has the potential to prolong the QT interval. Gilteritinib has been associated with QT prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
    Buprenorphine; Naloxone: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and buprenorphine is necessary. FDA-approved labeling for some buprenorphine products recommends avoiding use with any drug that has the potential to prolong the QT interval. Gilteritinib has been associated with QT prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
    Cabotegravir; Rilpivirine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and rilpivirine is necessary. Gilteritinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Carbamazepine: (Major) Avoid coadministration of gilteritinib and carbamazepine due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; carbamazepine is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Ceritinib: (Major) Consider an alternative to ceritinib during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, monitor for gilteritinib-related adverse reactions as well as monitoring periodic ECGs and serum electrolytes. Interrupt therapy, dose reduce, or discontinue treatment if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. In addition, both drugs have been associated with QT prolongation.
    Chloramphenicol: (Major) Consider an alternative to chloramphenicol during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Chloroquine: (Major) Avoid coadministration of chloroquine with gilteritinib due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Gilteritinib has been associated with QT prolongation.
    Chlorpromazine: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and chlorpromazine is necessary. Gilteritinib has been associated with QT prolongation. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP).
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Ciprofloxacin: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and ciprofloxacin is necessary. Gilteritinib has been associated with QT prolongation. Rare cases of QT prolongation and torsade de pointes (TdP) have been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Contraindicated) Use of gilteritinib with cisapride is contraindicated because of the potential for torsade de pointes (TdP). QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride. Gilteritinib has been associated with QT prolongation.
    Citalopram: (Major) Avoid coadministration of citalopram with gilteritinib due to the potential for decreased response to citalopram and an additive risk of QT prolongation. If concurrent therapy is considered essential, ECG monitoring is recommended. Gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs like citalopram that target these receptors. In addition, both drugs have been associated with QT prolongation.
    Clarithromycin: (Major) Consider an alternative to clarithromycin during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
    Clofazimine: (Major) Use caution and monitor electrocardiograms (ECGs) for evidence of QT prolongation if concurrent use of gilteritinib and clofazimine is necessary. Gilteritinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients receiving clofazimine in combination with QT prolonging medications.
    Clozapine: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and clozapine is necessary. Gilteritinib has been associated with QT prolongation. Clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Coadministration has the potential for additive QT prolongation.
    Cobicistat: (Major) Consider an alternative to cobicistat during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Cobimetinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with gilteritinib is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-glycoprotein substrate; gilteritinib is a P-gp inhibitor.
    Codeine; Phenylephrine; Promethazine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and promethazine is necessary. Both drugs have been associated with QT prolongation.
    Codeine; Promethazine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and promethazine is necessary. Both drugs have been associated with QT prolongation.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and gilteritinib in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Concomitant use may increase colchicine exposure; colchicine is a P-gp substrate and gilteritinib is a P-gp inhibitor. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken gilteritinib in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    Crizotinib: (Major) Avoid coadministration of crizotinib with gilteritinib due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. Gilteritinib has been associated with QT prolongation.
    Cyclosporine: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with gilteritinib is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a P-gp substrate and gilteritinib is a P-gp inhibitor.
    Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with gilteritinib is necessary in patients with creatinine clearance (CrCl) greater than 50 mL/minute. Avoid coadministration in patients with CrCl less than 50 mL/minute when dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery. Avoid coadministration in patients with CrCl less than 30 mL/minute in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function. Dabigatran is a P-gp substrate and gilteritinib is a P-gp inhibitor.
    Darunavir: (Major) Consider an alternative to darunavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Darunavir; Cobicistat: (Major) Consider an alternative to cobicistat during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. (Major) Consider an alternative to darunavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Consider an alternative to cobicistat during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. (Major) Consider an alternative to darunavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. (Moderate) Coadministration of tenofovir alafenamide with gilteritinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Consider an alternative to ritonavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with gilteritinib is necessary. Concurrent use may increase ombitasvir exposure. Ombitasvir is a substrate of P-gp and BCRP and gilteritinib is aP-gp and BCRP inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with gilteritinib is necessary. Concurrent use may increase paritaprevir exposure. Paritaprevir is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor. (Moderate) Monitor for increased dasabuvir-related adverse reactions, including QT prolongation, if coadministered with gilteritinib. Concurrent use may increase dasabuvir exposure. Dasabuvir is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor.
    Dasatinib: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and dasatinib is necessary. Gilteritinib has been associated with QT prolongation. In vitro studies have shown that dasatinib has the potential to prolong the QT interval. Coadministration has the potential for additive QT prolongation.
    Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving gilteritinib and degarelix as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Gilteritinib has also been associated with QT prolongation.
    Delavirdine: (Major) Consider an alternative to delavirdine during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Desflurane: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and halogenated anesthetics is necessary. Both gilteritinib and halogenated anesthetics have been associated with QT prolongation; coadministration has the potential for additive effects.
    Deutetrabenazine: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and deutetrabenazine is necessary. Gilteritinib has been associated with QT prolongation. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
    Dextromethorphan; Quinidine: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and quinidine is necessary. Gilteritinib has been associated with QT prolongation. Quinidine is associated with QT prolongation and torsade de pointes (TdP).
    Digoxin: (Moderate) Increase monitoring of serum digoxin concentrations and watch for potential signs and symptoms of clinical toxicity when starting, adjusting, or discontinuing gilteritinib. Concurrent use may increase digoxin exposure. Digoxin is a P-gp substrate with a narrow therapeutic index and gilteritinib is a P-gp inhibitor.
    Disopyramide: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and disopyramide is necessary. Gilteritinib has been associated with QT prolongation. Disopyramide has been associated with QT prolongation and torsade de pointes (TdP). Coadministration has the potential for additive QT prolongation.
    Dofetilide: (Major) Coadministration of dofetilide and gilteritinib is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Gilteritinib has been associated with QT prolongation.
    Dolasetron: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and dolasetron is necessary. Gilteritinib has been associated with QT prolongation. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Coadministration has the potential for additive QT prolongation.
    Dolutegravir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with gilteritinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor.
    Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with gilteritinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor.
    Dolutegravir; Rilpivirine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with gilteritinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor. (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and rilpivirine is necessary. Gilteritinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Donepezil: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and donepezil is necessary. Coadministration has the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Donepezil; Memantine: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and donepezil is necessary. Coadministration has the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with gilteritinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor.
    Doxorubicin Liposomal: (Major) Avoid coadministration of gilteritinib with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a P-gp substrate and gilteritinib is a P-gp inhibitor. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Doxorubicin: (Major) Avoid coadministration of gilteritinib with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a P-gp substrate and gilteritinib is a P-gp inhibitor. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Dronedarone: (Contraindicated) Use of gilteritinib with dronedarone is contraindicated because of the potential for torsade de pointes (TdP). Gilteritinib has been associated with QT prolongation. Dronedarone is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1,600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Major) Do not use droperidol and gilteritinib together due to the potential for additive QT prolongation. If coadministration cannot be avoided, use extreme caution; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal. Gilteritinib has also been associated with QT prolongation.
    Edoxaban: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of gilteritinib is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and gilteritinib is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with gilteritinib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of gilteritinib. Increased concentrations of edoxaban may occur during concomitant use of gilteritinib; monitor for increased adverse effects of edoxaban.
    Efavirenz: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and efavirenz is necessary. Gilteritinib has been associated with QT prolongation. QTc prolongation has been observed with the use of efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Coadministration of tenofovir disoproxil fumarate with gilteritinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor. (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and efavirenz is necessary. Gilteritinib has been associated with QT prolongation. QTc prolongation has been observed with the use of efavirenz.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with gilteritinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor. (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and efavirenz is necessary. Gilteritinib has been associated with QT prolongation. QTc prolongation has been observed with the use of efavirenz.
    Eliglustat: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and eliglustat is necessary. Gilteritinib has been associated with QT prolongation. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Consider an alternative to cobicistat during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. (Moderate) Coadministration of tenofovir alafenamide with gilteritinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Consider an alternative to cobicistat during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. (Moderate) Coadministration of tenofovir disoproxil fumarate with gilteritinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with gilteritinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor. (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and rilpivirine is necessary. Gilteritinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with gilteritinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor. (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and rilpivirine is necessary. Gilteritinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with gilteritinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with gilteritinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor.
    Encorafenib: (Major) Avoid coadministration of encorafenib and gilteritinib due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Gilteritinib has been associated with QT prolongation.
    Enflurane: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and halogenated anesthetics is necessary. Both gilteritinib and halogenated anesthetics have been associated with QT prolongation; coadministration has the potential for additive effects.
    Entrectinib: (Major) Avoid coadministration of entrectinib with gilteritinib due to the risk of QT prolongation. If coadministration is necessary, monitor for evidence of QT prolongation during treatment. Both entrectinib and gilteritinib have been associated with QT prolongation.
    Eribulin: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and eribulin is necessary. ECG monitoring is recommended. Gilteritinib and eribulin have both been associated with QT prolongation.
    Erythromycin: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and erythromcyin is necessary. Gilteritinib has been associated with QT prolongation. Erythromycin is associated with QT prolongation and torsade de pointes (TdP). Coadministration has the potential for additive cardiotoxicity.
    Erythromycin; Sulfisoxazole: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and erythromcyin is necessary. Gilteritinib has been associated with QT prolongation. Erythromycin is associated with QT prolongation and torsade de pointes (TdP). Coadministration has the potential for additive cardiotoxicity.
    Escitalopram: (Major) Avoid coadministration of escitalopram with gilteritinib if possible due to the potential for decreased response to escitalopram and additive QT prolongation. Gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs like escitalopram that target these receptors. In addition, both drug have been associated with QT prolongation.
    Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with gilteritinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-gp substrate and gilteritinib is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with gilteritinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; gilteritinib is a P-gp inhibitor.
    Ezogabine: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and ezogabine is necessary. Both drugs have been associated with QT prolongation; coadministration has the potential for additive effects.
    Fingolimod: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and fingolimod is necessary. Gilteritinib has been associated with QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
    Flecainide: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and flecainide is necessary. Gilteritinib has been associated with QT prolongation. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsade de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Fluconazole: (Contraindicated) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as gilteritinib, is contraindicated. Both drugs have been associated with QT prolongation.
    Fluoxetine: (Major) Avoid coadministration of fluoxetine with gilteritinib if possible due to the potential for additive QT prolongation and decreased response to fluoxetine. Gilteritinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Coadministration has the potential for additive cardiotoxicity. Additionally, gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs like fluoxetine that target these receptors.
    Fluphenazine: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and fluphenazine is necessary. Gilteritinib has been associated with QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Fluvoxamine: (Major) Avoid coadministration of fluvoxamine with gilteritinib if possible due to the potential for decreased response to fluvoxamine and additive QT prolongation. Gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs like fluvoxamine that target these receptors. Gilteritinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) has been reported during fluvoxamine postmarketing use.
    Fosamprenavir: (Major) Consider an alternative to fosamprenavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; fosamprenavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Foscarnet: (Major) Avoid concomitant use of foscarnet with gilteritinib due to the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of foscarnet.
    Fosphenytoin: (Major) Avoid coadministration of gilteritinib and fosphenytoin due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; fosphenytoin is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Fostemsavir: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and fostemsavir is necessary. Gilteritinib has been associated with QT prolongation. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, 4 times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
    Gemifloxacin: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and gemifloxacin is necessary. Gilteritinib has been associated with QT prolongation. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours after oral administration of gemifloxacin and may be dose-dependent.
    Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and gilteritinib together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Gilteritinib has been associated with QT prolongation.
    Glasdegib: (Major) Avoid coadministration of glasdegib with gilteritinib due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Gilteritinib has been associated with QT prolongation.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with coadministration of glecaprevir and gilteritinib as increased plasma concentrations of glecaprevir may occur resulting in increased risk of glecaprevir-related adverse events. Glecaprevir is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor. (Moderate) Monitor for an increase in pibrentasvir-related adverse effects if concomitant use of gilteritinib is necessary. Concomitant use may increase pibrentasvir exposure. Pibrentasvir is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor.
    Goserelin: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and goserelin is necessary. Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., goserelin) may prolong the QT/QTc interval. Gilteritinib has also been associated with QT prolongation.
    Granisetron: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and granisetron is necessary. Both drugs have been associated with QT prolongation.
    Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice due to increased gilteritinib exposure resulting in treatment-related adverse events. Gilteritinib is a CYP3A4 substrate; grapefruit is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Halogenated Anesthetics: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and halogenated anesthetics is necessary. Both gilteritinib and halogenated anesthetics have been associated with QT prolongation; coadministration has the potential for additive effects.
    Haloperidol: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and haloperidol is necessary. Gilteritinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
    Halothane: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and halogenated anesthetics is necessary. Both gilteritinib and halogenated anesthetics have been associated with QT prolongation; coadministration has the potential for additive effects.
    Histrelin: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and histrelin is necessary. Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval. Gilteritinib has also been associated with QT prolongation.
    Hydroxychloroquine: (Major) Avoid coadministration of gilteritinib and hydroxychloroquine due to the risk of increased QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Both drugs have been associated with QT prolongation.
    Hydroxyzine: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and hydroxyzine is necessary. Gilteritinib has been associated with QT prolongation. Postmarketing data indicate that hydroxyzine causes QT prolongation and torsade de pointes (TdP). Coadministration has the potential for additive QT effects.
    Ibutilide: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and ibutilide is necessary. Gilteritinib has been associated with QT prolongation. Ibutilide can cause QT prolongation and torsade de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
    Idelalisib: (Major) Consider an alternative to idelalisib during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Iloperidone: (Major) Avoid concomitant use of iloperidone with gilteritinib due to the potential for additive QT prolongation. Both drugs have been associated with QT prolongation; coadministration has the potential for additive effects.
    Indinavir: (Major) Consider an alternative to indinavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab with gilteritinib due to the potential for additive QT prolongation and torsade de pointes (TdP). If coadministration is unavoidable, obtain ECGs and prior to the start of treatment and periodically during treatment. Both drugs have been associated with QT prolongation.
    Isoflurane: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and halogenated anesthetics is necessary. Both gilteritinib and halogenated anesthetics have been associated with QT prolongation; coadministration has the potential for additive effects.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of gilteritinib and rifampin due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; rifampin is a combined P-gp and strong CYP3A4 inducer. Coadministration with rifampin decreased the gilteritinib AUC by 70% in a drug interaction study
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of gilteritinib and rifampin due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; rifampin is a combined P-gp and strong CYP3A4 inducer. Coadministration with rifampin decreased the gilteritinib AUC by 70% in a drug interaction study
    Itraconazole: (Major) Consider an alternative to itraconazole during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related adverse effects and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with gilteritinib if possible due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Gilteritinib has also been associated with QT prolongation.
    Ketoconazole: (Major) Consider an alternative to ketoconazole during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related adverse effects and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with gilteritinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Consider an alternative to clarithromycin during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
    Lapatinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with gilteritinib is necessary; correct electrolyte abnormalities prior to treatment. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience. Gilteritinib has been associated with QT prolongation. Coadministration has the potential for additive effects. Monitor for an increase in lapatinib-related adverse reactions if coadministration with gilteritinib is necessary. Lapatinib is a P-gp substrate and gilteritinib is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
    Lefamulin: (Major) Avoid coadministration of lefamulin with gilteritinib as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Gilteritinib has been associated with QT prolongation. The concurrent use of gilteritinib with oral lefamulin may increase lefamulin exposure and adverse effects; gilteritinib may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and gilteritinib is a P-gp inhibitor.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with gilteritinib due to the potential for additive QT prolongation. Both drugs have been associated with QT prolongation.
    Letermovir: (Moderate) Consider an alternative to letermovir in patients also receiving cyclosporine during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration of all 3 drugs is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor; however, when administered with cyclosporine the effect may be similar to a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Leuprolide: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and leuprolide is necessary as concurrent use may increase the risk of QT prolongation. Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval. Gilteritinib has also been associated with QT prolongation.
    Leuprolide; Norethindrone: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and leuprolide is necessary as concurrent use may increase the risk of QT prolongation. Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval. Gilteritinib has also been associated with QT prolongation.
    Levofloxacin: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and levofloxacin is necessary. Gilteritinib has been associated with QT prolongation. Levofloxacin has been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin.
    Levoketoconazole: (Major) Consider an alternative to ketoconazole during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related adverse effects and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
    Lithium: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and lithium is necessary. Both drugs have been associated with QT prolongation.
    Lofexidine: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and lofexidine is necessary. Monitor ECG. Both drugs have been associated with QT prolongation.
    Lonafarnib: (Major) Consider an alternative to lonafarnib during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Loperamide: (Moderate) Monitor for additive QT prolongation and loperamide-associated adverse reactions (e.g., CNS effects) if concurrent use of gilteritinib and loperamide is necessary. Gilteritinib has been associated with QT prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and gilteritinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
    Loperamide; Simethicone: (Moderate) Monitor for additive QT prolongation and loperamide-associated adverse reactions (e.g., CNS effects) if concurrent use of gilteritinib and loperamide is necessary. Gilteritinib has been associated with QT prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and gilteritinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with gilteritinib due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Both drugs have been associated with QT prolongation. (Major) Consider an alternative to ritonavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Lovastatin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with gilteritinib is necessary. Concomitant use may increase lovastatin exposure. Lovastatin is a P-gp substrate; gilteritinib is a P-gp inhibitor.
    Lovastatin; Niacin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with gilteritinib is necessary. Concomitant use may increase lovastatin exposure. Lovastatin is a P-gp substrate; gilteritinib is a P-gp inhibitor.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of gilteritinib and lumacaftor; ivacaftor due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; lumacaftor; ivacaftor is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of gilteritinib and lumacaftor; ivacaftor due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; lumacaftor; ivacaftor is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Macimorelin: (Major) Avoid concomitant use of macimorelin with gilteritinib due to the potential for additive QT prolongation. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended.
    Maprotiline: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and maprotiline is necessary. Gilteritinib has been associated with QT prolongation. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
    Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with gilteritinib is necessary. Concomitant use may increase maraviroc exposure. Maraviroc is a P-gp substrate; gilteritinib is a P-gp inhibitor.
    Mefloquine: (Moderate) Monitor for additive QT prolongation if concurrent use of gilteritinib and mefloquine is necessary. Gilteritinib has been associated with QT prolongation. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval. Monitor for an increase in mefloquine-related adverse effects if concomitant use of gilteritinib is necessary. Concomitant use may increase mefloquine exposure. Mefloquine is a P-gp substrate and gilteritinib is a P-gp inhibitor.
    Meperidine; Promethazine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and promethazine is necessary. Both drugs have been associated with QT prolongation.
    Methadone: (Major) Use extreme caution and monitor for additive QT prolongation if concurrent use of gilteritinib and methadone is necessary; carefully assess treatment risks versus benefits. Gilteritinib has been associated with QT prolongation. Methadone is considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Metronidazole: (Moderate) Concomitant use of metronidazole and gilteritinib may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Midostaurin: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and midostaurin is necessary. Consider obtaining periodic electrocardiograms. Both drugs have been associated with QT prolongation.
    Mifepristone: (Major) Consider an alternative to mifepristone during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related adverse effects and cardiac toxicity. To minimize the risk of QT prolongation, the lowest effective dose of mifepristone should always be used. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; mifepristone is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
    Mirtazapine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and mirtazapine is necessary. Gilteritinib has been associated with QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Mobocertinib: (Major) Concomitant use of mobocertinib and gilteritinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Morphine: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with gilteritinib is necessary; decrease the dose of morphine as necessary. Morphine is a P-gp substrate and gilteritinib is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
    Morphine; Naltrexone: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with gilteritinib is necessary; decrease the dose of morphine as necessary. Morphine is a P-gp substrate and gilteritinib is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
    Moxifloxacin: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and moxifloxacin is necessary. Gilteritinib has been associated with QT prolongation. Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Naldemedine: (Moderate) Monitor for naldemedine-related adverse reactions if coadministered with gilteritinib. Naldemedine plasma concentrations may increase during concomitant use. Naldemedine is a P-gp substrate; gilteritinib is a P-gp inhibitor.
    Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid coadministration of sirolimus with gilteritinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and gilteritinib is a P-gp inhibitor.
    Nefazodone: (Major) Consider an alternative to nefazodone during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Nelfinavir: (Major) Consider an alternative to nelfinavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Niacin; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with gilteritinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; gilteritinib is a P-gp inhibitor.
    Nilotinib: (Major) Avoid concomitant use of nilotinib with gilteritinib due to the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
    Nirmatrelvir; Ritonavir: (Major) Consider an alternative to ritonavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Norfloxacin: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and norfloxacin is necessary. Gilteritinib has been associated with QT prolongation. Quinolones have been associated with risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of norfloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Octreotide: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and octreotide is necessary. Gilteritinib has been associated with QT prolongation. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (TdP), the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval. Until further data are available, it is suggested to use octreotide cautiously in patients receiving drugs which prolong the QT interval.
    Ofloxacin: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and ofloxacin is necessary. Gilteritinib has been associated with QT prolongation. Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and olanzapine is necessary. Gilteritinib has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Olanzapine; Fluoxetine: (Major) Avoid coadministration of fluoxetine with gilteritinib if possible due to the potential for additive QT prolongation and decreased response to fluoxetine. Gilteritinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Coadministration has the potential for additive cardiotoxicity. Additionally, gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs like fluoxetine that target these receptors. (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and olanzapine is necessary. Gilteritinib has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Olanzapine; Samidorphan: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and olanzapine is necessary. Gilteritinib has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Consider an alternative to ritonavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with gilteritinib is necessary. Concurrent use may increase ombitasvir exposure. Ombitasvir is a substrate of P-gp and BCRP and gilteritinib is aP-gp and BCRP inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with gilteritinib is necessary. Concurrent use may increase paritaprevir exposure. Paritaprevir is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor.
    Ondansetron: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and ondansetron is necessary. ECG monitoring is recommended. Gilteritinib has been associated with QT prolongation. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Osilodrostat: (Moderate) Monitor ECGs in patients receiving osilodrostat with gilteritinib as concurrent use may increase the risk of QT prolongation. Osilodrostat is associated with dose-dependent QT prolongation. Gilteritinib has also been associated with QT prolongation.
    Osimertinib: (Major) Avoid coadministration of gilteritinib with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Gilteritinib has also been associated with QT prolongation.
    Oxaliplatin: (Major) Monitor ECGs and electrolytes in patients receiving oxaliplatin concomitantly with gilteritinib; correct electrolyte abnormalities prior to administration of oxaliplatin. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have been reported with oxaliplatin use in postmarketing experience. Gilteritinib has also been associated with QT prolongation.
    Ozanimod: (Major) In general, do not initiate ozanimod in patients taking gilteritinib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Gilteritinib has been associated with QT prolongation
    Pacritinib: (Major) Concomitant use of pacritinib and gilteritinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Paliperidone: (Major) Avoid concomitant use of paliperidone with gilteritinib due to the potential for additive QT prolongation. If coadministration is necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. Both paliperidone and gilteritinib have been associated with QT prolongation. Torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of paliperidone overdose.
    Panobinostat: (Major) Coadministration of panobinostat and gilteritinib is not recommended. Both drugs have been associated with QT prolongation.
    Paroxetine: (Major) Avoid coadministration of paroxetine with gilteritinib if possible due to the potential for decreased response to paroxetine. Gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs like paroxetine that target these receptors.
    Pasireotide: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and pasireotide is necessary. Gilteritinib has been associated with QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
    Pazopanib: (Major) Concomitant use of pazopanib with gilteritinib is not advised due to the potential for additive QT prolongation. If use together is necessary, closely monitor the patient.Taking these medication together may increase pazopanib exposure. Pazopanib is a P-gp and BCRP substrate; gilteritinib is a P-gp and BCRP inhibitor.
    Pentamidine: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and pentamidine is necessary. Gilteritinib and systemic pentamidine have both been associated with QT prolongation.
    Perphenazine: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and perphenazine is necessary. Gilteritinib has been associated with QT prolongation. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Perphenazine; Amitriptyline: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and perphenazine is necessary. Gilteritinib has been associated with QT prolongation. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Phenobarbital: (Major) Avoid coadministration of gilteritinib and phenobarbital due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; phenobarbital is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of gilteritinib and phenobarbital due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; phenobarbital is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Phenytoin: (Major) Avoid coadministration of gilteritinib and phenytoin due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; phenytoin is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Pimavanserin: (Major) Avoid concomitant use of pimavanserin with gilteritinib due to the potential for additive QT prolongation. Both drugs have been associated with QT prolongation.
    Pimozide: (Contraindicated) Use of gilteritinib with pimozide is contraindicated because of the potential for torsade de pointes (TdP). Gilteritinib has been associated with QT prolongation. Pimozide is associated with a well-established risk of QT prolongation and TdP.
    Pitavastatin: (Moderate) Monitor for an increase in pitavastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with gilteritinib is necessary. Concomitant use may increase pitavastatin exposure. Pitavastatin is a P-gp substrate; gilteritinib is a P-gp inhibitor.
    Pitolisant: (Major) Avoid coadministration of pitolisant with gilteritinib as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Gilteritinib has also been associated with QT prolongation.
    Ponesimod: (Major) In general, do not initiate ponesimod in patients taking gilteritinib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If treatment initiation is considered, seek advice from a cardiologist and monitor for signs and symptoms of infection. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Gilteritinib has been associated with QT prolongation.
    Posaconazole: (Major) Consider an alternative to posaconazole during treatment with gilteritinib due to a risk of increased exposure of both medications and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib or posaconazole-related adverse effects. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate and P-gp inhibitor; posaconazole is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation. Monitor for an increase in posaconazole-related adverse reactions if coadministration with gilteritinib is necessary. Concomitant use may increase posaconazole exposure. Posaconazole is a P-gp substrate; gilteritinib is a P-gp inhibitor.
    Primaquine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and primaquine is necessary. Both drugs have been associated with QT prolongation.
    Primidone: (Major) Avoid coadministration of gilteritinib and primidone due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; primidone is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Probenecid; Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and gilteritinib in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Concomitant use may increase colchicine exposure; colchicine is a P-gp substrate and gilteritinib is a P-gp inhibitor. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken gilteritinib in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    Procainamide: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and procainamide is necessary. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Gilteritinib has also been associated with QT prolongation.
    Prochlorperazine: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and prochlorperazine is necessary. Gilteritinib has been associated with QT prolongation. Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Promethazine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and promethazine is necessary. Both drugs have been associated with QT prolongation.
    Promethazine; Dextromethorphan: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and promethazine is necessary. Both drugs have been associated with QT prolongation.
    Promethazine; Phenylephrine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and promethazine is necessary. Both drugs have been associated with QT prolongation.
    Propafenone: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and propafenone is necessary. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Gilteritinib has also been associated with QT prolongation.
    Pseudoephedrine; Triprolidine: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and tripolidine is necessary. Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval. Gilteritinib has also been associated with QT prolongation.
    Quetiapine: (Major) Avoid concomitant use of quetiapine with gilteritinib due to the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances.
    Quinidine: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and quinidine is necessary. Gilteritinib has been associated with QT prolongation. Quinidine is associated with QT prolongation and torsade de pointes (TdP).
    Quinine: (Major) Avoid concomitant use of quinine with gilteritinib due to the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
    Ranolazine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and ranolazine is necessary. Gilteritinib has been associated with QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Monitor for an increase in ranolazine-related adverse reactions if coadministration with gilteritinib is necessary and consider a ranolazine dosage adjustment. Concomitant use may increase ranolazine exposure. Ranolazine is a P-gp substrate; gilteritinib is a P-gp inhibitor.
    Relugolix: (Major) Avoid concomitant use of relugolix and oral gilteritinib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. Monitor for evidence of QT prolongation if concurrent use of gilteritinib and relugolix is necessary. Gilteritinib has been associated with QT prolongation. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. If concomitant use is necessary, administer gilteritinib at least 6 hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of gilteritinib is required; if treatment is interrupted for more than seven days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Relugolix is a P-gp substrate and gilteritinib is a P-gp inhibitor.
    Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral gilteritinib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. Monitor for evidence of QT prolongation if concurrent use of gilteritinib and relugolix is necessary. Gilteritinib has been associated with QT prolongation. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. If concomitant use is necessary, administer gilteritinib at least 6 hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of gilteritinib is required; if treatment is interrupted for more than seven days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Relugolix is a P-gp substrate and gilteritinib is a P-gp inhibitor.
    Ribociclib: (Major) Avoid coadministration of ribociclib with gilteritinib due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Gilteritinib has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with gilteritinib due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Gilteritinib has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Rifampin: (Major) Avoid coadministration of gilteritinib and rifampin due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; rifampin is a combined P-gp and strong CYP3A4 inducer. Coadministration with rifampin decreased the gilteritinib AUC by 70% in a drug interaction study
    Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with gilteritinib is necessary. Rifaximin is a P-gp substrate and gilteritinib is a P-gp inhibitor. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Coadministration with one P-gp inhibitor decreased the efflux ratio of rifaximin by greater than 50%. Concomitant use with another P-gp inhibitor increased the Cmax and AUC of rifaximin by 83-fold and 124-fold.
    Rilpivirine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and rilpivirine is necessary. Gilteritinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with gilteritinib; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and gilteritinib is a P-gp inhibitor.
    Risperidone: (Moderate) Use caution and closely monitor for additive QT prolongation if concurrent use of gilteritinib and risperidone is necessary. Gilteritinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) during risperidone therapy have primarily occurred in the overdosage setting.
    Ritonavir: (Major) Consider an alternative to ritonavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Romidepsin: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and romidepsin is necessary. Consider monitoring of electrolytes and ECGs at baseline and periodically during treatment. Both drugs have been associated with QT prolongation.
    Rosuvastatin: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with gilteritinib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and gilteritinib is a BCRP inhibitor.
    Rosuvastatin; Ezetimibe: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with gilteritinib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and gilteritinib is a BCRP inhibitor.
    Saquinavir: (Contraindicated) Coadministration of gilteritinib and saquinavir is contraindicated due to the risk of additive QT prolongation and other gilteritinib-related toxicities. Gilteritinib is a CYP3A4 substrate and a P-gp inhibitor; saquinavir is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Gilteritinib has been associated with QT prolongation. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Selpercatinib: (Major) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with gilteritinib is necessary due to the risk of additive QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Gilteritinib has been associated with QT prolongation.
    Sertraline: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and sertraline is necessary. Gilteritinib has been associated with QT prolongation. Sertraline's FDA-approved labeling recommends avoiding concomitant use with drugs known to prolong the QTc interval; however, the risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure). Additionally, gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs like sertraline that target these receptors.
    Sevoflurane: (Major) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and halogenated anesthetics is necessary. Both gilteritinib and halogenated anesthetics have been associated with QT prolongation; coadministration has the potential for additive effects.
    Silodosin: (Major) Avoid coadministration of silodosin and gilteritinib due to the potential for increased silodosin exposure. In vitro data indicate that silodosin is a P-glycoprotein substrate; gilteritinib is a P-gp inhibitor.
    Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with gilteritinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; gilteritinib is a P-gp inhibitor.
    Simvastatin; Sitagliptin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with gilteritinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; gilteritinib is a P-gp inhibitor.
    Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving gilteritinib due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Gilteritinib has also been associated with QT prolongation.
    Sirolimus: (Major) Avoid coadministration of sirolimus with gilteritinib as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a P-gp substrate and gilteritinib is a P-gp inhibitor.
    Solifenacin: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and solifenacin is necessary. Gilteritinib has been associated with QT prolongation. Solifenacin has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined.
    Sorafenib: (Major) Avoid coadministration of sorafenib with gilteritinib due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Both drugs are associated with QTc prolongation.
    Sotalol: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and sotalol is necessary. Gilteritinib has been associated with QT prolongation. Sotalol administration is associated with QT prolongation and torsade de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of gilteritinib and St. John's Wort due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; St. John's Wort is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
    Sunitinib: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and sunitinib is necessary. Both drugs have been associated with QT prolongation.
    Tacrolimus: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with gilteritinib. Gilteritinib has been associated with QT prolongation. Tacrolimus may also prolong the QT interval and cause torsade de pointes.
    Talazoparib: (Major) Avoid coadministration of gilteritinib with talazoparib if possible due to increased talazoparib exposure. If concomitant use is unavoidable, monitor for an increase in talazoparib-related adverse reactions. Talazoparib is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor. The effect of concomitant administration of BCRP inhibitors on the pharmacokinetics of talazoparib has not been studied; however, BCRP inhibitors may increase talazoparib exposure. Coadministration with other P-gp inhibitors increased talazoparib exposure by 8% to 45%.
    Tamoxifen: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and tamoxifen is necessary. Gilteritinib has been associated with QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Telavancin: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and telavancin is necessary. Both drugs have been associated with QT prolongation.
    Telithromycin: (Major) Consider an alternative to telithromycin during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related adverse effects and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; telithromycin is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
    Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with gilteritinib is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and gilteritinib is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
    Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with gilteritinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor.
    Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with gilteritinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor.
    Tenofovir, PMPA: (Moderate) Coadministration of tenofovir disoproxil fumarate with gilteritinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor.
    Tetrabenazine: (Major) Avoid concomitant use of tetrabenazine with gilteritinib due to the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Tetrabenazine causes a small increase in the corrected QT interval (QTc).
    Thioridazine: (Contraindicated) Use of gilteritinib with thioridazine is contraindicated because of the potential for torsade de pointes (TdP). Gilteritinib has been associated with QT prolongation. Thioridazine is associated with a well-established risk of QT prolongation and TdP.
    Ticagrelor: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with gilteritinib as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-gp substrate and gilteritinib is a P-gp inhibitor.
    Tipranavir: (Major) Consider an alternative to tipranavir during treatment with gilteritinib. Concurrent use may increase gilteritinib and/or tipranavir exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib and tipranavir adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate and a P-gp inhibitor; tipranavir is a strong CYP3A4 inhibitor and a P-gp substrate. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Tolterodine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and tolterodine is necessary. Gilteritinib has been associated with QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    Topotecan: (Major) Avoid coadministration of gilteritinib with oral topotecan due to increased topotecan exposure; gilteritinib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Toremifene: (Major) Avoid coadministration of gilteritinib with toremifene due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Gilteritinib has also been associated with QT prolongation.
    Trazodone: (Major) Avoid concomitant use of trazodone with gilteritinib due to the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes (TdP).
    Triclabendazole: (Moderate) Monitor ECGs in patients receiving triclabendazole with gilteritinib as concurrent use may increase the risk of QT prolongation. Transient prolongation of the mean QTc interval was noted on the ECG recordings in dogs administered triclabendazole. Gilteritinib has also been associated with QT prolongation.
    Trifluoperazine: (Minor) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and trifluoperazine is necessary. Gilteritinib has been associated with QT prolongation. Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Triprolidine: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and tripolidine is necessary. Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval. Gilteritinib has also been associated with QT prolongation.
    Triptorelin: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and triptorelin is necessary. Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval. Gilteritinib has also been associated with QT prolongation.
    Tucatinib: (Major) Consider an alternative to tucatinib during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with gilteritinib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a substrate of the BCRP and P-gp drug transporters; gilteritinib is a BCRP and P-gp inhibitor.
    Vandetanib: (Major) Avoid coadministration of vandetanib with gilteritinib due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Gilteritinib has also been associated with QT prolongation.
    Vardenafil: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and vardenafil is necessary. Gilteritinib has been associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Vemurafenib: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and vemurafenib is necessary. ECG monitoring is recommended. Both drugs have been associated with QT prolongation.
    Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with gilteritinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of gilteritinib. Venetoclax is a P-gp substrate; gilteritinib is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    Venlafaxine: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and venlafaxine is necessary. Gilteritinib has been associated with QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Vincristine Liposomal: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of gilteritinib is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and gilteritinib is a P-gp inhibitor.
    Vincristine: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of gilteritinib is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and gilteritinib is a P-gp inhibitor.
    Voclosporin: (Moderate) Concomitant use of voclosporin and gilteritinib may increase the risk of QT prolongation. Consider interventions to minimize the risk of progression to torsades de pointes (TdP), such as ECG monitoring and correcting electrolyte abnormalities, particularly in patients with additional risk factors for TdP. Voclosporin has been associated with QT prolongation at supratherapeutic doses. Gilteritinib has been associated with QT prolongation.
    Voriconazole: (Major) Consider an alternative to voriconazole during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related adverse effects and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
    Vorinostat: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and vorinostat is necessary. Both drugs have been associated with QT prolongation.
    Ziprasidone: (Major) Avoid concomitant use of ziprasidone with gilteritinib due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.

    PREGNANCY AND LACTATION

    Pregnancy

    Gilteritinib may cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies. Females of reproductive potential should avoid becoming pregnant while taking gilteritinib. Discuss the potential hazard to the fetus if a patient becomes pregnant while taking this drug. Although gilteritinib has not been evaluated in pregnant women, fetal toxicity occurred when pregnant rats received a gilteritinib dose resulting in approximately 0.4-times the exposure that was observed in humans who received the recommended dose. Fetal toxicity in this animal study included embryo-fetal death; decreased fetal body and placental weight; decreased numbers of ossified sternebrae and sacral and caudal vertebrae; and an increased incidence of fetal gross external (e.g., anasarca, local edema, exencephaly, cleft lip, cleft palate, short tail, and umbilical hernia), visceral (e.g., microphthalmia, atrial and/or ventricular defects, malformed/absent kidney, and malpositioned adrenal gland and ovary), and skeletal (e.g., sternoschisis, absent rib, fused rib, fused cervical arch, misaligned cervical vertebra, and absent thoracic vertebra) abnormalities.[63787]

    It is not known if gilteritinib or its active metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Because there is a potential for adverse reactions in nursing infants from gilteritinib, women should be advised against breast-feeding during gilteritinib therapy and for 2 months after the last dose.[63787]

    MECHANISM OF ACTION

    Gilteritinib is a small molecule that inhibits multiple receptor tyrosine kinases, including FMS-like tyrosine kinase 3 (FLT3). It demonstrates the ability to inhibit FLT3 receptor signaling and proliferation in cells exogenously expressing FLT3 including FLT3-ITD, tyrosine kinase domain (TKD) mutations FLT3-D835Y and FLT3-ITD-D835Y, and it induces apoptosis in leukemic cells expressing FLT3-ITD. In patients with relapsed or refractory AML administered gilteritinib, substantial (greater than 90%) inhibition of FLT3 phosphorylation was rapid (within 24 hours after the first dose) and sustained, as characterized by an ex vivo plasma inhibitor activity (PIA) assay.[63787]
     
    Gilteritinib inhibits 5-Hydroxytryptamine receptor 2B (5HT2B), also known as serotonin receptor 2B, and sigma nonspecific receptors in vitro. Concomitant use of gilteritinib may reduce the effects of drugs that target these receptors.[63787]

    PHARMACOKINETICS

    Gilteritinib is administered orally. It is approximately 94% bound to human plasma proteins in vivo and is primarily bound to human serum albumin in vitro. The population mean (%CV) estimates of apparent central and peripheral volume of distribution is 1,092 L (9.22%) and 1,100 L (4.99%), respectively, which may indicate extensive tissue distribution. Gilteritinib is primarily metabolized via CYP3A4 in vitro. At steady state, the primary metabolites in humans include M17 (formed via N-dealkylation and oxidation), M16 (formed via N-dealkylation), and M10 (formed via N-dealkylation); however, none of these 3 metabolites exceed 10% of overall parent exposure. Single radiolabeled dose studies show 64.5% of the total administered gilteritinib dose is excreted in the feces. Of the total radiolabeled dose, 16.4% was recovered in the urine as unchanged drug and metabolites. The estimated half-life is 113 hours and the estimated apparent clearance is 14.85 L/hour.
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic cation transporter (OCT)-1
    Gilteritinib is a CYP3A4 substrate. It did not significantly inhibit CYP3A4 in a drug interaction study; gilteritinib increased the AUC of a sensitive CYP3A substrate by approximately 10% when coadministered. It did not significantly induce the multidrug and toxin extrusion (MATE)-1 transporter in a drug interaction study; gilteritinib decreased the AUC of a MATE-1 substrate by less than 10% when coadministered. In vitro, gilteritinib is a substrate of P-gp and BCRP and a P-gp, BCRP, and OCT-1 inhibitor.[63787]

    Oral Route

    The time to maximum gilteritinib concentration (Tmax) is approximately between 4 and 6 hours after the dose in the fasted state. Gilteritinib exposure (Cmax and AUC) increases proportionally with once daily doses ranging from 20 mg to 450 mg (0.27 to 3.75 times the recommended dose). The mean steady-state Cmax is 374 ng/mL and AUC is 6943 ng x h/mL. Steady-state plasma concentrations are reached within 15 days of dosing with an approximate 10-fold accumulation.[63787]
     
    Effects of food: In healthy adults administered a single 40 mg gilteritinib dose (0.3 times the recommended dose), the Cmax decreased by 26% and the AUC decreased by less than 10% when coadministered with a high-fat meal (approximately 800 to 1000 calories with 500 to 600 fat calories) compared to a fasted state. The median Tmax was delayed 2 hours when administered with a high-fat meal.[63787]